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PHILADELPHIA -- Researchers at Fox Chase Cancer Center have made a crucial discovery that may help physicians better diagnose and treat children with Hirschsprung disease, a debilitating and sometimes life-threatening ailment that causes bowel obstruction and involves an array of genetic changes. The report will be published in the advance online publication of Nature Genetics on May 30.

Developmental biologist Myung K. Shin, PhD, and his colleagues have identified a critical regulatory region for the development of the enteric nervous system, which plays a vital role in gastrointestinal functions. Genetic mutations in this region may lead to incomplete development of the enteric nervous system, often causing Hirschsprung disease.

Hirschsprung disease is a hereditary disorder that affects about one in every 5,000 newborns. The disease results from the absence of neural cells, or neurons, in the large intestine, which causes severe bowel obstruction.

So far, the only treatment for this disease is early diagnosis and surgery to remove the diseased segment of the bowel. In general, the prognosis for most children after surgery is very good. However, a significant percentage of patients develop long-term complications or die of complications associated with the disease.

"Currently, ten genes or loci have been linked with Hirschsprung disease," Shin pointed out, "but these mutations do not account for a large percentage of cases."

Shin and his colleagues have isolated a regulatory region affecting the gene for endothelin receptor B (EDNRB), one of the primary genes known to be mutated in Hirschsprung disease.

"Now it appears that mutations in genomic sequences involved in regulating EDNRB could explain Hirschsprung disease as well," said Shin. "Our results in mice strongly suggest that the regulatory region we've discovered is a prime target for identifying potential regulatory mutations in patients with Hirschsprung disease. These mutations could explain some cases of the disease not accounted for by previously known genetic changes."

Furthermore, the regulatory sequences discovered in Shin's studies depend on another Hirschsprung-susceptible gene, SOX10, and provide an explanation as to why mutations in SOX10 cause Hirschsprung disease.

Shin was drawn to study Hirschsprung disease because his laboratory has focused on understanding the underlying mechanism mediated by EDNRB. To better understand how defects in this signaling pathway lead to human diseases, Shin's lab has used mouse models to study the early embryonic stages in which these genes are required to form the complex neuronal network needed by the intestine.

"The enhancer sequence we have discovered is important for regulating the EDNRB gene," said Shin. "This sequence is highly conserved between mice and humans. Learning how EDNRB gene expression is normally regulated may help clarify how it is misregulated in cancer and help in designing therapies against these diseases."

In addition to Hirschsprung disease, some patients with mutations at EDNRB have associated syndromes, such as abnormal pigmentation, with white spots in the skin and hair, and hearing loss. Defects in the EDNRB signaling pathway also play a part in other major diseases, including cancer, hypertension and cardiovascular disorders.

Research elsewhere has shown that inappropriate expression of EDNRB can promote cell proliferation and metastasis of tumors, including melanomas and breast and prostate cancer cells. Shin's laboratory has studies in progress to locate the enhancer specific to the EDNRB pathway in pigment-producing cells (melanocytes), from which the serious skin cancer melanoma arises.

Shin's co-authors on the new paper include scientific technician Lei Zhu, M.S., and postdoctoral associate Hyung-Ok Lee, PhD, of Fox Chase; former student assistant ChaRandle S. Jordan, now at Stanford University School of Medicine; and V. Ashley Cantrell and E. Michelle Southard-Smith, PhD, of Vanderbilt University.

Grants to Shin's lab from the National Institutes of Health and Pew Scholars Program in Biomedical Sciences and institutional support from Fox Chase Cancer Center and the National Cancer Institute helped support this work.

Fox Chase Cancer Center, part of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence four consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. For more information, call 1-888-FOX CHASE or (1-888-369-2427).

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